Chamillionaire appeared on the remix for Weezer's song "Can't Stop Partying", from their album Raditude. He also joined Weezer for live performances as Lil Wayne, who is featured on the original version of the track, was convicted on gun possession charges and was unable to perform. On December 11, 2009, Chamillionaire performed a set for "Fort Hood Community Strong", an event described as a day of "healing, fun and entertainment" for those placed at the Fort Hood military base who were affected by the shooting that took place on November 5, 2009, killing 13 people. Other performers at the event included Nick Jonas, Dana Carvey and Zac Brown Band.
On December 23, 2009, Chamillionaire announced via his YouTube page that he would be initiating a new mixtape, Major Pain, through his website on February 2, 2010. Due to the 2010 NBA All-Star Game taking place in Dallas, Texas, Chamillionaire released a new song, "The Main Event", on February 11, 2010, via free download. It features fellow Texas rappers Paul Wall, Slim Thug and Dorrough. "Every artist on the song with me has independent hustle and strength in the streets," he said. "It's an All-Star song, so what better place to shoot the video than All-Star Weekend, right here in our own backyard." It was later released to iTunes on June 8, 2010.
Chamillionaire met Mark Suster in 2009, an American entrepreneur and venture capitalist who is a managing partner at Upfront Ventures. Chamillionaire became and invested in his online video talent agency, Maker Studios. On November 4, 2009, Chamillionaire also launched the Global Innovation Tournament 2009 at the Stanford Memorial Auditorium, Stanford University with Quincy Jones III as part of the Stanford Entrepreneurial Thought Leaders Seminar Series.